Glucocorticoids regulate the metabolic hormone FGF21 in a feed-forward loop

Area of Science:

• Endocrinology
• Metabolic Regulation
• Molecular Biology

Background:

• Fibroblast growth factor 21 (FGF21) and glucocorticoids (GCs) are key regulators of the adaptive starvation response.
• Previous studies indicated FGF21 elevates corticosterone levels in mice via central mechanisms.
• The interaction and reciprocal regulation between FGF21 and GCs were not fully elucidated.

Purpose of the Study:

• To investigate the bidirectional interplay between FGF21 and glucocorticoids in coordinating the starvation response.
• To elucidate the molecular mechanisms underlying GC-mediated regulation of Fgf21 expression.
• To understand how this hormonal axis impacts gluconeogenesis during fasting.

Main Methods:

• Analysis of gene expression in adrenal glands and liver tissues.
• Investigation of hormone secretion in response to hormonal stimulation (ACTH).
• Chromatin immunoprecipitation assays to identify receptor binding sites.
• In vivo and in vitro studies using mouse models and primary hepatocytes.

Main Results:

• FGF21 upregulates genes for GC synthesis and enhances ACTH-stimulated corticosterone secretion.
• GCs directly induce Fgf21 expression in the liver through the glucocorticoid receptor (GR).
• GR binds to a distal enhancer element and cooperates with PPAR-α to drive Fgf21 transcription.

Conclusions:

• FGF21 and GCs engage in a reciprocal feed-forward regulatory loop.
• This interaction bypasses normal negative feedback on the hypothalamic-pituitary-adrenal axis.
• The FGF21-GC axis supports sustained gluconeogenesis during prolonged starvation.